This invention relates to a process for producing a sequential polyamino acid resin having a high degree of polymerization and a constant amino acid sequence as separating unit in the resin.
Proteins for constituting living bodies and peptide hormones have sequences of various kinds of amino acids with a constant order and molecular weights of from several thousands to several hundred thousands. But detailed studies on the structure of these proteins and peptide hormones revealed that special sequential order of two to four kinds of amino acids forms repeating units in most cases. Further, in the case of peptide hormones having physiological activity, the sequence of all the amino acids is not necessary but the sequence of special several kinds of amino acids controls the physiological activity in many cases. For example, it is well known that collagen which is a kind of protein for constituting a living body has sequential polyamino acid moieties in large amounts containing the sequence of residues of 3 kinds of amino acids, i.e., X-prolyl-glycyl-(wherein X is a residue of amino acid such as proline, hydroxyproline, etc.), and muscle protein myosin has leucyl-glycyl moieties in large amounts. In peptide hormones, gastrin, for example, is a hormone having the sequence of 17 amino acids but only 4 special amino acids sequence is sufficient for exhibiting the action of hormone.
Therefore, if high molecular weight polyamino acids having these special amino acid sequences as repeating units can be produced, they can be used for medical treatments in the form of fibers or film as materials having excellent suitability for living bodies when they are synthetic polyamino acid resins having functions and structures similar to the objected proteins, or can be used as medicines having prolonged and effective pharmacological efficiency by gradually decomposing at special portions on the affected parts when they are high molecular weight polyamino acid resins having peptides with physiological activity as repeating units due to their stability.
Polyamino acids can be synthesized by polymerization of an amino acid-N-carboxy anhydride (NCA). According to this NCA method, the composition of the produced polyamino acid is determined unitarily by reactivities of individual amino acid-NCAs and proportions of charged amino acid-NCAs. But the composition ratio of individual amino acids in the polymer is only determined and this does not mean that a sequential polyamino acid constructing from a required amino acid sequence can be obtained.
In order to overcome such a disadvantage, there have been proposed various polymerization methods by using as monomer activated peptides having the desired amino acid sequences. For example, there are proposed a method for polymerizing L-prolyl-L-leucyl-glycine.hydrochloride in the presence of dicyclohexylcarbodiimide and an alkali (hereinafter referred to as "DCC method"), a method for polymerizing a chlorinated phenyl ester of L-prolyl-L-leucyl-glycine.trifluoroacetate in the presence of an organic amine (hereinafter referred to as "active ester method") [H. Kitaoka, S. Sakakibara, H. Tani: Bull, Chem. Soc. Japan, 31(7), 802-807 (1958); Japanese Patent Appln Kokai (Laid-Open) No. 137495/77]. There is also proposed a method wherein a peptide active ester is used as monomer in a coupling method of amino acid [B. J. Johnson: J. Pharm. Sci. 63(3), 313-327 (1974); "Chemistry and Biochemistry of Amino Acids, Peptides and Proteins" edited by B. Weinstein, vol. 4, pp 29-63, Marcel Dekker Inc., N.Y., 1977].
But the molecular weights of the resulting polymers obtained by the above-mentioned methods are several thousands or less in average molecular weight with an inherent viscosity (.eta.inh) (C=0.5) of 0.1 to 0.2 at most. Such molecular weights are so low that these polymers cannot be used as synthetic protein. Therefore, it has generally been admitted that a polyamino acid having a very high molecular weight cannot be produced.